Extracorporeal blood circulation requires heparin anticoagulation to provide blood compatibility. However, in acutely ill patients at high risk of bleeding, the use of heparin often leads to life-threatening hemorrhagic complications. To avoid such complications, protamine, a heparin antagonist, is generally administered at the conclusion of the extracorporeal procedure to counteract heparin's anticoagulant activity. Although protamine has been approved by FDA for such therapeutic use, it is nevertheless a relatively toxic compound. But as long as there are no alternatives to control the more serious bleeding problems, protamine remains in use in conjunction with heparin therapy despite its toxic effects. A method is suggested in this proposal which would potentially eliminate the bleeding risks associated with heparinization, and would at the same time minimize the toxic effects resulting from heparin neutralization with protamine. This approach consists of a blood filter containing immobilized protamine (i.e., a protamine filter) which could be placed at the termination of any extracorporeal device. The protamine filter would bind and selectively remove heparin before it returned to the patient from the extracorporeal circuit, and meanwhile, would maintain the protamine treatment at regions outside the patient's body, thereby minimizing protamine's toxic effects. The specific aims of this proposal are: (i) to develop and construct a blood compatible protamine filter, (ii) to test the function of the filter in vitro, (iii) to evaluate the performance and hemocompatibility of the filter in vivo, and (iv) to examine the effectiveness of the proposed system in preventing heparin complications and protamine toxicities.